Proteases are an important family of enzymes released from granulocytes, leukocytes and macrophages which are functional in a many standard biological activities, including digestion, formation and dissolution of blood clots, the formation of active forms of hormones, the immune reaction to foreign cells and organisms in pathological conditions. It has been reported that proteases from granulocytes and macrophages are responsible for chronic tissue destruction associated with inflammation, including rheumatoid arthritis and emphysema.
Azurophilic granules of human polymorphonuclear leukocytes (PMN) and macrophages release human leukocyte elastase (HLE), a serine protease which has a serine at its active site (Travis, J.; Salvesen, G. S. Annu. Rev. Biochem. 1983, 52,655). HLE has been reported to be capable of degrading the connective tissue component elastin as well as other connective tissue substrates and is implicated in the pathogenesis of a variety of inflammatory diseases, including pulmonary emphysema, rheumatoid arthritis, spondylitis, psoriasis, osteoarthritis, chronic bronchitis, cystic fibrosis, and respiratory distress syndrome. (Mittman, C., Ed., Pulmonary Emphysema and Proteolysis, Academic Press: New York, 1972; Janoff, A. Am. Rev. Respir. Dis. 1985, 132, 417; Morrison, H. M. Clin. Sci. 1987, 72, 151; Sprung et al., N. Engl. J. Med. 1981, 304 1301; Cochrane et al., J. Clin. Invest. 1983, 71, 754; Snider, G. L. Drug Dev. Res. 1987, 10,235; Jackson, et al., Eur. J. Respir. Dis. 1984, 65, 114; Suter et al., J. Infect. Dis. 1984, 149, 523; Velvart, M. Rheumatol. Int. 1981, 1, 121; and Ekerot et al., Adv. Exp. Med. Biol. 1984, 167, 335).
Under normal conditions, the proteolytic activity of proteases, including HLE, in the extracellular environment is inhibited by an excess of natural inhibitors, predominantly .alpha..sub.1 protease inhibitor (.alpha..sub.1 PI) and .alpha..sub.2 macroglobulin. The natural inhibitors bind to the elastase and block the active site of the enzyme and because of their configurations, bind tightly to the enzyme. .alpha..sub.1 PI is a glycoprotein found in human serum and exhibits inhibitory activity against elastase from the pancreas and from polymorphonuclear leukocytes. The inhibitor is hydrolyzed by the proteases to form a stable acyl enzyme in which the active site is no longer available.
However, pathological conditions can arise which disrupt the elastase-anti-elastase balance, resulting in an uncontrolled proteolysis of structural tissue, primarily in the lung and joints (Travis et al., supra). Marked reduction in serum .alpha..sub.1 PI, either genetic or due to oxidants, has been associated with pulmonary emphysema which is characterized by a progressive loss of lung elasticity and respiratory distress. The loss of lung elasticity is caused by the progressive, uncontrolled proteolysis of the structure of the lung tissue by proteases such as elastase from leukocytes. (Powers, J. C., TIBS, 211, 1976). In addition, elastase has also been reported to participate in the progressive deterioration of articular cartilage resulting in rheumatoid arthritis. (Menninger, H. et al., Biological Functions of Proteinases, H. Holzer and H. Tschesche, eds. Springer-Verlag, Berlin, Heidelberg, N.Y., 1979, pp.196-206).
Accordingly, therapeutic compounds which act as elastase inhibitors have been developed. Among the most effective elastase inhibitors are cephalosporin sulfone derivatives.
U.S. Pat. No. 4,547,371 discloses the use of substituted cephalosporin sulfones as elastase inhibitors which have the structure shown below. ##STR1## The C-2 position which is designated as Q is described as being hydrogen, C.sub.1-6 alkyl, substituted or unsubstituted methylene, or unsubstituted or substituted phenylthio C.sub.1-6 alkyl or phenylsulfonyl C.sub.1-6 alkyl.
Hagmann et al., (1989) Eur. J. Med. Chem. 24:599-604 discloses the inhibition of human leukocyte elastase by C-2 substituted cephalosporin sulfones. The C-2 position in the structure shown below which is designated as R.sub.1 is substituted with H, CH.sub.2, .alpha.-CH.sub.3, .beta.-CH.sub.3, CH.sub.2 SPh, --CH.sub.2 CH.sub.2 N.sub.2 --, --CH.sub.2 CH.sub.2 -- or .alpha.-OCH.sub.3. ##STR2##
European Patent No. 0337704 discloses the use of 4-acylcephem sulfones as elastase inhibitors which have the structure shown below. ##STR3## The C-2 position which is designated as R.sub.3 is described as being a methylene group (.dbd.CH.sub.2) or .dbd.CHR.sup.IV, wherein R.sub.IV is either C.sub.1 -C.sub.4 alkyl or phenyl, carboxy, C.sub.1 -C.sub.4 alkyloxycarbonyl.
The present inventors have discovered that 2-[(substituted)methylene]cephalosporin sulfones, particularly 2-[(heteroaryl substituted)methylene]cephalosporin sulfones are highly useful as elastase inhibitors and thus can be used in the treatment of inflammatory and degenerative diseases caused by proteolytic enzymes in mammals. The present inventors have also discovered that the compounds of the present invention are highly useful as anti-thrombin agents in the prevention, control and treatment of blood clotting.